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is a significant concern for physicians. Central; d* Q" t3 C- d, U. s
precocious puberty (CPP), which is mediated
+ a' t5 l) Y @" f( Z" L6 S, b" L uthrough the hypothalamic pituitary gonadal axis, has: |* ?0 |! S. y, U+ Y% L0 c
a higher incidence of organic central nervous system
1 j& |& d0 `, \- X2 E# ylesions in boys.1,2 Virilization in boys, as manifested- w3 k M7 T6 m) {
by enlargement of the penis, development of pubic" U" A+ C; t+ N: z( v2 B
hair, and facial acne without enlargement of testi-
! z- j& E2 |* fcles, suggests peripheral or pseudopuberty.1-3 We0 Y( u+ e+ C2 H3 x
report a 16-month-old boy who presented with the
8 c% V5 \. S7 k* Qenlargement of the phallus and pubic hair develop-
% G( T- ]) y2 p. |# b3 N9 }4 N) Vment without testicular enlargement, which was due
4 h" Y3 R+ j3 ?! Zto the unintentional exposure to androgen gel used by2 }* Q- ]% B7 I8 y( C! ]
the father. The family initially concealed this infor-
$ P4 g& F- ]! W, T+ K; Pmation, resulting in an extensive work-up for this
% D, r6 `! [$ z, b% v- Qchild. Given the widespread and easy availability of( j8 a$ e/ c: U1 x/ ~; h4 V0 Z
testosterone gel and cream, we believe this is proba- s5 t# L- U4 \- v+ {
bly more common than the rare case report in the# d* U# _/ y0 g' `6 R. @6 H
literature.47 h) b; E. g. i( e( |! d) @1 j1 K
Patient Report# n! R) `: E* T$ |6 P
A 16-month-old white child was referred to the
2 b! j) H# d3 `, c h% g' nendocrine clinic by his pediatrician with the concern* B" g j1 _: W) S; m R$ m
of early sexual development. His mother noticed5 J" |4 Y0 ]0 T# A# G) p/ X$ V
light colored pubic hair development when he was) b) o0 ]: _0 d1 v5 u, \4 ~
From the 1Division of Pediatric Endocrinology, 2University of, P; O/ Q( c$ s) ^; r, j
South Alabama Medical Center, Mobile, Alabama.4 s+ [0 y; {( g) T5 [" q6 @
Address correspondence to: Samar K. Bhowmick, MD, FACE,1 n9 H5 \% U5 A. c+ e# T
Professor of Pediatrics, University of South Alabama, College of/ ]" f4 D6 H7 T+ _0 R1 K1 J
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
5 s) p/ Z K2 Ge-mail: [email protected]. v& s+ }: Y( f! b! M; W: F7 x
about 6 to 7 months old, which progressively became& n+ e0 o7 ~# a: H# Y/ }: ?5 @
darker. She was also concerned about the enlarge-/ c, t. `6 |$ r7 }. B1 z
ment of his penis and frequent erections. The child
g: F- t! d% t/ M6 U& f# cwas the product of a full-term normal delivery, with& R& e; d6 B% G' m
a birth weight of 7 lb 14 oz, and birth length of
8 x5 V* V' q5 U% j% q3 s20 inches. He was breast-fed throughout the first year6 K) E ?; e$ L5 _
of life and was still receiving breast milk along with
. @2 G) s8 X: d( h1 g2 @solid food. He had no hospitalizations or surgery,
2 J' z* i0 E- d$ I% L0 G7 {2 qand his psychosocial and psychomotor development0 |: j$ }) V' k$ x1 |5 ?2 Z
was age appropriate.
; i' R* q" Y8 o- j7 c$ l% X$ v& {The family history was remarkable for the father," j+ w/ j' s# ^# F7 g1 ^( y# d
who was diagnosed with hypothyroidism at age 16,
, B9 C/ {2 C) ]) a0 c( @; ewhich was treated with thyroxine. The father’s
r$ V6 K, e) A# R5 |/ h, Oheight was 6 feet, and he went through a somewhat5 {: N* J4 A$ _1 f h3 X4 H, c
early puberty and had stopped growing by age 14.( ?& ~( r; |& @4 p" l6 g
The father denied taking any other medication. The
4 Z6 A/ L5 e8 x' [9 Qchild’s mother was in good health. Her menarche
1 l5 u4 G; ^; Y1 n! @, Ywas at 11 years of age, and her height was at 5 feet
" @; r# ^: z- c% P% T5 inches. There was no other family history of pre-4 H; o" L/ r7 t2 y" V* R
cocious sexual development in the first-degree rela-
2 t" G/ s) M+ ?tives. There were no siblings.
) D5 G0 m( [1 k$ v, O4 m% D. PPhysical Examination8 K% {) [6 y' \4 ^" S! S7 k" K- M
The physical examination revealed a very active,- M% h" F2 V d; U
playful, and healthy boy. The vital signs documented
4 [! z) {" d2 q7 g6 _a blood pressure of 85/50 mm Hg, his length was
7 K6 y) C' @. F7 @" \90 cm (>97th percentile), and his weight was 14.4 kg L( b4 z; O8 p& O# y& ~
(also >97th percentile). The observed yearly growth
8 Z! y! g8 d( u, Q& d. Z7 \2 b' Qvelocity was 30 cm (12 inches). The examination of9 H& u- m7 ?% u& f+ R
the neck revealed no thyroid enlargement.' Z! z. q4 }' F t8 P0 U# J' Y
The genitourinary examination was remarkable for5 `: a$ h- A# g" Y- G8 O; l
enlargement of the penis, with a stretched length of# W* ~ }/ P, b6 @0 a
8 cm and a width of 2 cm. The glans penis was very well7 X3 v) }3 H% u1 S
developed. The pubic hair was Tanner II, mostly around
) p. h' }; @; u# W9 T y6 a: {8 |! g540. v/ i# D0 `2 p" ~
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from, l: _2 @ w: |
the base of the phallus and was dark and curled. The
+ f2 A E' F5 {, F0 U3 Wtesticular volume was prepubertal at 2 mL each.
9 ]+ _9 ^( T# C7 uThe skin was moist and smooth and somewhat, ?4 a- ?1 d# M4 p* P
oily. No axillary hair was noted. There were no
3 o6 S# b6 c( _/ T; jabnormal skin pigmentations or café-au-lait spots.
) M1 [$ p O7 j1 e4 f e R3 ANeurologic evaluation showed deep tendon reflex 2+
, P: r( h; r8 a3 m o! J: gbilateral and symmetrical. There was no suggestion, r: w9 e# y2 P0 G4 {6 a5 N& J' @
of papilledema.
6 o% Y8 y5 o$ S: S7 s& d; hLaboratory Evaluation+ P5 O9 p$ K* d7 ]
The bone age was consistent with 28 months by
6 w3 H, J1 X" b; I" K: Musing the standard of Greulich and Pyle at a chrono-
7 O0 z- Y8 K/ u' Plogic age of 16 months (advanced).5 Chromosomal
* P9 V/ z5 @* h8 ~% ^! ]karyotype was 46XY. The thyroid function test
+ {: z. A t+ |9 G8 e# [0 m/ d( P" wshowed a free T4 of 1.69 ng/dL, and thyroid stimu- _' t* M% J8 Z; t/ f/ O/ l7 O
lating hormone level was 1.3 µIU/mL (both normal).
. u9 W* w4 b7 m+ Y/ X4 V( UThe concentrations of serum electrolytes, blood" F+ O5 Q Y7 l: r
urea nitrogen, creatinine, and calcium all were
# U V( s- N2 C# X* ]5 Hwithin normal range for his age. The concentration
: e8 |9 O0 y. q- dof serum 17-hydroxyprogesterone was 16 ng/dL ~8 j) a0 J/ `0 D
(normal, 3 to 90 ng/dL), androstenedione was 20' `! } j7 T3 K+ C/ U" m
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
1 S+ |1 b$ @- I$ R6 m1 Bterone was 38 ng/dL (normal, 50 to 760 ng/dL),
# t W+ X" V! Q7 j; ?desoxycorticosterone was 4.3 ng/dL (normal, 7 to
1 ^+ }& O5 ], q; A! Z& u: b1 e49ng/dL), 11-desoxycortisol (specific compound S)# x/ ^$ K3 B2 ^- H" b
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
- e2 F6 D [4 Stisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total3 d) M" R9 Z( i* ?( {5 |0 H! k
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),* I: c& u+ b( b
and β-human chorionic gonadotropin was less than
9 ^, I) n. B2 S! t( _5 mIU/mL (normal <5 mIU/mL). Serum follicular" ?0 j: B" m3 f
stimulating hormone and leuteinizing hormone
8 m7 ?; o2 o6 P4 B0 @$ @& dconcentrations were less than 0.05 mIU/mL
- n6 ]' g- l) d4 J(prepubertal).
& i1 y7 l# p) n) E- r! JThe parents were notified about the laboratory
0 T' d' G2 k- Q4 o( G. Fresults and were informed that all of the tests were
% P% T7 s$ A5 R- E* O5 V6 s- qnormal except the testosterone level was high. The
+ }5 T9 v N; F# u4 D$ b' g' C R/ [follow-up visit was arranged within a few weeks to A% y+ Z$ V# @6 X% z& H7 M! x
obtain testicular and abdominal sonograms; how-
6 p; o1 _( Z; }1 K0 zever, the family did not return for 4 months.
3 [7 S3 K: ?, H& X% ^- `Physical examination at this time revealed that the
* P/ l: K, z( o. H3 uchild had grown 2.5 cm in 4 months and had gained
: O$ c& ~9 S3 q7 c" W2 kg of weight. Physical examination remained% }/ T" R$ j8 x9 p9 r; o
unchanged. Surprisingly, the pubic hair almost com-8 J' l8 j0 z3 {( w/ f1 p: ~) q! l7 K
pletely disappeared except for a few vellous hairs at5 M. Z3 T2 S( s) K: U
the base of the phallus. Testicular volume was still 28 ?6 z- M2 l2 ]
mL, and the size of the penis remained unchanged.6 j, S5 { p ]) D, k( ~
The mother also said that the boy was no longer hav-" g. }3 b/ U/ Q. A) I
ing frequent erections.
! l3 w2 K( `& GBoth parents were again questioned about use of& t& n$ A: S- x+ H$ B
any ointment/creams that they may have applied to8 K2 W3 ^9 Q9 N. Y
the child’s skin. This time the father admitted the
- }9 J$ e# D( b8 Z( m& D q1 Z1 MTopical Testosterone Exposure / Bhowmick et al 541
4 N% D$ V+ {' o# z& nuse of testosterone gel twice daily that he was apply-
1 Q& F! ]+ m( _7 C/ W( Eing over his own shoulders, chest, and back area for4 g* s! j- A& B# I$ ^" u
a year. The father also revealed he was embarrassed, x# n) y3 U7 ~; f0 b
to disclose that he was using a testosterone gel pre-
6 U. }9 ?* S1 Hscribed by his family physician for decreased libido8 a7 c8 I! ?, T0 f7 O) v
secondary to depression.
7 z7 S% g m& Y! Y$ l! jThe child slept in the same bed with parents.
: G% Y2 h; f& h( A6 o9 k) ZThe father would hug the baby and hold him on his x- a6 l2 i' F
chest for a considerable period of time, causing sig-
- v) f" n* q% z8 j( dnificant bare skin contact between baby and father.2 L: u3 L; V/ [; u: q( ~
The father also admitted that after the phone call,0 e# n; Z1 u$ c6 H, V" _
when he learned the testosterone level in the baby
4 T4 \+ D1 ]8 M& W2 J& |; kwas high, he then read the product information
( o2 F8 o& A8 e2 }& w- m& ?packet and concluded that it was most likely the rea-
* }* L+ y* Q! Q: V6 kson for the child’s virilization. At that time, they
2 d/ o9 \7 N* g" _3 ^decided to put the baby in a separate bed, and the
; u& f4 ]/ c! l6 _+ `father was not hugging him with bare skin and had$ s1 @. n" _9 D) s+ f. T+ E
been using protective clothing. A repeat testosterone
! a9 Q" x& |" q# n. [- c3 Vtest was ordered, but the family did not go to the
6 i, o3 X* Z5 j8 q9 [( U" Vlaboratory to obtain the test.4 n9 @3 R- |& M
Discussion
4 J, U8 x* u$ j, T6 f; @# @8 p; }Precocious puberty in boys is defined as secondary
1 b( k3 w8 g& R0 `* O6 K0 a5 Psexual development before 9 years of age.1,44 P+ G$ a# u( r& `2 Q! l
Precocious puberty is termed as central (true) when
6 H! g0 S/ V! M$ {( M: j! kit is caused by the premature activation of hypo-
# Y$ l. ^; u' Uthalamic pituitary gonadal axis. CPP is more com-
7 D$ f( r$ W) r4 b$ Q2 [mon in girls than in boys.1,3 Most boys with CPP
j: c" w* ]0 L6 w' ?may have a central nervous system lesion that is1 f+ L8 }% E1 I2 y$ R
responsible for the early activation of the hypothal-+ c8 ]' {4 D& M, h) o
amic pituitary gonadal axis.1-3 Thus, greater empha-6 ` c( J# k6 n6 m+ E; S9 o5 Z1 P+ {
sis has been given to neuroradiologic imaging in
/ X$ G, p Y( O) o% E8 V% Q- ^boys with precocious puberty. In addition to viril-
3 X) ?) s+ l9 @- x* k& Hization, the clinical hallmark of CPP is the symmet-
e' J S* N8 d S& `! Erical testicular growth secondary to stimulation by
8 c7 f9 \- I" fgonadotropins.1,3
& k/ x, c0 @, f1 `# X$ \+ ZGonadotropin-independent peripheral preco-
* q5 E1 s, _6 v" M4 y2 Dcious puberty in boys also results from inappropriate
* U1 [( q. j. r$ S( Pandrogenic stimulation from either endogenous or- \; }0 A: u1 Y
exogenous sources, nonpituitary gonadotropin stim-0 ^: v4 j9 | X! t- J- z
ulation, and rare activating mutations.3 Virilizing" M) O W4 x2 ]- r+ O7 O
congenital adrenal hyperplasia producing excessive1 @8 g E) N8 e6 \3 B$ K4 p
adrenal androgens is a common cause of precocious
3 ^8 ~0 o/ S4 ^puberty in boys.3,40 F5 n9 R' j+ Q1 _
The most common form of congenital adrenal6 F" I$ p/ O& N( g2 S, C: f
hyperplasia is the 21-hydroxylase enzyme deficiency.
; |/ ?' i& {8 {! P+ GThe 11-β hydroxylase deficiency may also result in
, R' u! v K4 z3 n- H9 vexcessive adrenal androgen production, and rarely,
( ^- l( p- c: j4 e0 r( ]! v9 _an adrenal tumor may also cause adrenal androgen {1 A" q9 p y$ u$ o+ z
excess.1,3
( E5 P! P/ \& J0 V6 \0 U+ ^at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from+ [' F) q+ @0 \7 b0 C* g. d. x% j
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
' F% p/ [4 f2 ]' ?5 h _A unique entity of male-limited gonadotropin-
! X; {& k5 R K6 O; Bindependent precocious puberty, which is also known5 u$ ~& `: [4 B
as testotoxicosis, may cause precocious puberty at a
# ?! f" a8 y0 K. L! cvery young age. The physical findings in these boys! f6 m* H5 z! o7 ]
with this disorder are full pubertal development,4 J/ _; u- u! |' U) o* j
including bilateral testicular growth, similar to boys
9 |2 O8 j. H/ i4 }with CPP. The gonadotropin levels in this disorder6 F* u+ K' |- n a+ l
are suppressed to prepubertal levels and do not show
1 C$ M6 m% l8 Tpubertal response of gonadotropin after gonadotropin-/ _% ~! l% `5 q3 ~1 f; d( r
releasing hormone stimulation. This is a sex-linked# a# T# f' s; }1 f, T$ s
autosomal dominant disorder that affects only1 s! |$ l9 j( M6 ~7 I5 [- z
males; therefore, other male members of the family
; O) e& k& r$ K# Z$ v' Jmay have similar precocious puberty.3, x4 V( ~% ?2 ~
In our patient, physical examination was incon-
" g R( ^6 [) ysistent with true precocious puberty since his testi-
7 w' ~; p% e4 {3 o) |cles were prepubertal in size. However, testotoxicosis
: _, @6 u: K0 }was in the differential diagnosis because his father' H; l. f, S. n" Z9 z2 V# K; U
started puberty somewhat early, and occasionally,
1 i6 b" Y1 H% I3 Ptesticular enlargement is not that evident in the
2 W! m8 m" X( G* u9 f) Cbeginning of this process.1 In the absence of a neg-, f4 E, L0 d& j
ative initial history of androgen exposure, our1 k7 {) e( p, {" V7 z
biggest concern was virilizing adrenal hyperplasia,
& {/ W% \7 R7 Z6 J6 Meither 21-hydroxylase deficiency or 11-β hydroxylase
* D' V( J9 d7 kdeficiency. Those diagnoses were excluded by find-
- i8 A- G; V$ J) o3 x9 b7 Ring the normal level of adrenal steroids.
, D/ t6 @7 q" G; n/ j! fThe diagnosis of exogenous androgens was strongly
+ p7 C2 _1 S4 Isuspected in a follow-up visit after 4 months because
% \+ `, v% F6 v' ythe physical examination revealed the complete disap-
& c) g* I3 Z8 \ b& ]: zpearance of pubic hair, normal growth velocity, and
& }( X) r& C3 \# ~# W: h& mdecreased erections. The father admitted using a testos-
, v E- t6 Q- p& S& Xterone gel, which he concealed at first visit. He was" B2 V4 D9 D; O0 m
using it rather frequently, twice a day. The Physicians’, q/ G3 ^- p% s& h# ^
Desk Reference, or package insert of this product, gel or* r, H5 e: G7 \" S8 V. Y
cream, cautions about dermal testosterone transfer to
; ^4 p V' E- h: k9 wunprotected females through direct skin exposure.
( Y# u/ ]+ _' ?Serum testosterone level was found to be 2 times the. j/ Y: L. h$ G8 N2 J
baseline value in those females who were exposed to% |8 |7 O, [0 Q- _! I( t& r3 k
even 15 minutes of direct skin contact with their male! ]$ G. b1 h1 i' R' z
partners.6 However, when a shirt covered the applica-) h, _( f) h7 m
tion site, this testosterone transfer was prevented.+ a' C1 h8 q" i
Our patient’s testosterone level was 60 ng/mL,# M+ j, g9 ^' X
which was clearly high. Some studies suggest that: K6 q/ K* z6 F3 n+ O' [
dermal conversion of testosterone to dihydrotestos-0 Q* a# l6 j3 L$ B! L/ ~$ e- |( C
terone, which is a more potent metabolite, is more5 @3 E# a# f2 {
active in young children exposed to testosterone
: R7 a( U2 u9 A E- A; qexogenously7; however, we did not measure a dihy-
" p9 J& c( \9 R/ X2 p. [# |drotestosterone level in our patient. In addition to
( m6 e" a4 I5 \virilization, exposure to exogenous testosterone in; V. {8 S. X9 M/ U8 I- R. C v
children results in an increase in growth velocity and+ u, n3 L4 Y! B
advanced bone age, as seen in our patient.
% {6 W: j, E! Y8 F! FThe long-term effect of androgen exposure during
/ c: n+ `4 o$ p% searly childhood on pubertal development and final( j4 s ^, \# @
adult height are not fully known and always remain4 M! G+ a9 o# a5 f: A4 }
a concern. Children treated with short-term testos-
, v9 T a0 z% V% `* kterone injection or topical androgen may exhibit some
, M# b2 H0 i! l: Sacceleration of the skeletal maturation; however, after
4 H! D4 s/ q# j) Y+ y1 R& ?cessation of treatment, the rate of bone maturation* D8 G) ?* s/ }- k! i
decelerates and gradually returns to normal.8,9
' c) q8 o: `8 y7 w5 kThere are conflicting reports and controversy
. s( O" |8 } K9 R T& q C5 cover the effect of early androgen exposure on adult- H P* u8 Y* d# i
penile length.10,11 Some reports suggest subnormal
$ e1 w: K2 h- ^& a5 uadult penile length, apparently because of downreg-$ Z1 w4 t$ F! D) }8 H4 L9 k" Q8 e
ulation of androgen receptor number.10,12 However,
7 ~+ E2 R% Q1 ?& E6 [Sutherland et al13 did not find a correlation between
( g$ B* e( w* }* Gchildhood testosterone exposure and reduced adult
' c# o: D$ u; j6 spenile length in clinical studies.
9 _+ N* H' z# H( S, C% _Nonetheless, we do not believe our patient is
& Q$ Z* Z& K* X2 I! Wgoing to experience any of the untoward effects from3 b% z% a/ C8 @
testosterone exposure as mentioned earlier because3 x% {, z7 s; {4 l6 T
the exposure was not for a prolonged period of time.' [" e4 V5 {8 ], Y5 D3 M
Although the bone age was advanced at the time of5 d# G4 s: w; A
diagnosis, the child had a normal growth velocity at
% \5 v0 m3 `3 b) }" j2 Othe follow-up visit. It is hoped that his final adult( ~' S# w# V; T: R6 r3 }
height will not be affected.! A0 _' B* s8 T9 Y; |+ J8 v. }
Although rarely reported, the widespread avail-3 [) c; T# L: }) J1 K/ c* P
ability of androgen products in our society may A, ^" E/ @. r! T) V- Q& _
indeed cause more virilization in male or female
, |3 N1 ?; D8 z+ j* Dchildren than one would realize. Exposure to andro-
6 z( z- a% i3 n* C0 f7 \ egen products must be considered and specific ques-
1 `; v9 p# t7 j- b( Rtioning about the use of a testosterone product or
4 x% N4 m0 Z% e0 n# V2 V# D) b7 fgel should be asked of the family members during. z$ Q5 `0 S! U$ I6 \: M; g
the evaluation of any children who present with vir-5 p6 B1 i7 X# j, _' ~- N3 ?
ilization or peripheral precocious puberty. The diag-, `+ U2 J l' g& d7 C5 w" \
nosis can be established by just a few tests and by: I5 K) `, t' I
appropriate history. The inability to obtain such a4 t, r7 R( a% y' W
history, or failure to ask the specific questions, may
) Z9 O8 J* t! v0 Q6 r: oresult in extensive, unnecessary, and expensive# Q! v5 p# b, s9 p% v3 Q- |- h
investigation. The primary care physician should be
2 Z( C5 Q2 T; z2 Raware of this fact, because most of these children
: u% |, \6 v, O# ]% n7 Fmay initially present in their practice. The Physicians’. A; G0 W2 N/ I7 m3 H5 @
Desk Reference and package insert should also put a
8 ]9 v' @, F* J/ P: y9 cwarning about the virilizing effect on a male or
[. V4 B, Y7 S: j! ~4 i$ |) bfemale child who might come in contact with some-
. I4 v% _: U, y& Vone using any of these products.
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puberty in children with tumours of the suprasellar pineal
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: e! F1 |! l- ?5. Greulich WW, Pyle SI, eds. Radiographic Atlas of
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8 N% p. I C5 E4 R( }7 K6. Physicians’ Desk Reference. Androgel 1% testosterone,
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Economics Company, Inc; 2004:3239-3241.
( x% ?" Y# s5 b1 G+ _& ^; ]5 p7. Klugo RC, Cerny JC. Response of micropenis to topical" E7 v7 x9 J8 N+ S
testosterone and gonadotropin. J Urol. 1978;119:. {! J K% N& @* E( V
667-668.+ j% g5 g: ^9 o& G/ k7 G7 W
8. Guthrie RD, Smith DW, Graham CB. Testosterone
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